The unifying theme of this revised P01 Grant renewal is a cellular and molecular approach to intellectual and developmental disabilities in an attempt to uncover processes contributing to neuronal synaptic damage, particularly in Down syndrome (DS). Three inter-related projects are planned. They all study overstimulation of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR), leading to synaptic damage and cognitive dysfunction in children. Here we show that oligomers of AP protein, as found in DS with or without Alzheimer's disease, can trigger excessive stimulation of extrasynaptic NMDARs, contributing to loss of thin dendritic spines, with resulting compromise of synaptic function and cognitive ability. This P01 Grant is credited with developing the first clinically-tolerated NMDAR antagonist, Memantine, which we showed is an uncompetitive, open-channel blocker with a relatively fast off-rate, accounting for its clinical tolerability. We then developed new, more effective drugs, called NitroMemantines, for the treatment of neonatal hypoxic- ischemic brain damage. NitroMemantines act on NMDAR channels (like Memantine) but also donate NO species to react at nitrosylation sites on the NMDAR to further downregulate excessive activity better than Memantine. Additionally, we plan to develop novel drugs based on structure-function relationships of the NR3 family of NMDAR subunits, which were discovered under the auspices of this PO1 grant. Project I will study the basis of NitroMemantine action and develop new NMDAR antagonists based on NR3 structure- function. Project II will test NitroMemantine vs. Memantine to prevent synaptic damage and cognitive deficits in DS using human fetal and IPS cell-based models in culture and the mouse Ts65Dn model in vivo. Project III will complement Project II by taking a genetic rather than a pharmacologic approach to downregulating excessive NMDAR activity or its downstream effects. Accordingly, Project III will test genetic models of altered NR3 genes or the downstream takusan family of genes for neuroprotection in similar in vitro and in vivo models of DS as in Project 11. The CORE supports administration, statistics, tissue culture, and crystallography/modeling of NMDAR subunits and functional sites, all critical to the proposed Projects.